A. Keith Stewart, MB, ChB: So throughout this meeting there were quite a few abstracts addressing clinical trials with which an attempt was made to change the natural history of smoldering myeloma. And one of them that caught my attention was the use of elotuzumab in combination with lenalidomide and dexamethasone. Do you want to comment on that, Adriana?

Adriana Rossi, MD: Well I think it’s nice, both the ELO study, ELO/RD and the IXARD, which were the 2… Ixazomib, thank you. They give us an opportunity. We’re moving earlier and treating patients before they have end organ damage, which is much more palatable now that therapies are so well tolerated. And what I really liked about both of these studies is that they’re adding on correlative studies and other ways for us to inform and learn about the disease process. And, what is it? Can we distinguish which patients do benefit, which ones could maybe get away without therapy, and that maybe it’s not such a clear cut-off but it’s a plasmacytosis, an exact number? You know I think we have good data and guidelines to support certain clear definitions but in clinical practice I think we all sort of have a sense of this patient is about to get themselves into trouble and maybe someone with 50% rather than 60% in the marrow would be appropriate. But I really look forward to all of this other data, like the exome sequencing and RNA data that could maybe help us understand the patients better.

A. Keith Stewart, MB, ChB: So my take on these trials is that they all of course show a fairly high response rate. They all seem to trend towards decreasing the time to which you get myeloma. Were there any, Tom, in particular, that stood out for you that were interesting?

Thomas Martin, MD: Yeah. So what I would say about those 2 trials are that both actually in my mind had relatively low rates of complete response [CR]. And I think if we’re going to treat smoldering myeloma, and we’re not going to call it smoldering any more, we’re going to call it myeloma, let’s treat it with our best regimens. And we’ll talk more later about what our best regimens are for newly diagnosed myeloma, but I think I would be more aggressive in this patient population. And I think that we have data with RVd [lenalidomide, bortezomib, and dexamethasone] and a lot of data now with KRd [carfilzomib plus lenalidomide and dexamethasone], and now we’re getting data with quadruplets. And so I think my take on this is that if I’m going to treat them, I’m going to treat them with a more potent induction regimen.

A. Keith Stewart, MB, ChB: Do you feel that they’re being undertreated with these regimens then?

Thomas Martin, MD: I’m not sure if it’s undertreated, but I think we could treat them better and try to induce a higher rate of complete response. I mean at the end of the day we’re going to be looking at minimal residual disease—MRD-negativity. I don’t think we’re going to get the same MRD negativity from these 2 regimens—ELO, lenalidomide, and dexamethasone, or ixazomib, lenalidomide, and dexamethasone.

A. Keith Stewart, MB, ChB: So I listened to the presentation yesterday, particularly the elotuzumab, lenalidomide, and dexamethasone presentation, Faith, and one thing that struck me was that there were 2 deaths out of the 50 patients, but both looked to me like they were likely therapy related, with diabetic ketoacidosis and myocardial infarction. I guess that’s the concern, right? You’re overtreating and people who have a decade-long expectation of survival are being put at risk. What do you think of that?

Faith Davies, MD, MBBCh, MRCP, FRCPath: That’s why we have to really tighten up those criteria. I think that we know these drugs are safe and effective, but we really have to make sure that we’re treating those patients that are myeloma, and are not going to be those stable cases. So there’s definitely some fine-tuning there. And I think my own feeling is that we’re never going to get very strict guidance, and to some extent, it is going to be a little bit more of a gut feeling. I think as you said earlier, you know maybe at 50% and 60% and saying, “This is 50% and this is 60%, I shouldn’t treat,” I’m not sure that’s the way it’s going to be. I think it’s going to be a little bit more of see the patients and monitor them really closely so that we can pick out the best one.

A. Keith Stewart, MB, ChB: And Adriana you mentioned the correlative studies. I mean one thing that would concern me would potentially be breeding clonal evolution and drug resistance, which I guess we’ll learn from those studies.

Adriana Rossi, MD: We will, and, again, looking not only at the plasma cells. I think the more we learn about myeloma, it’s not really about the tumor cells themselves but the effect they have on the neighborhood. And what is the behavior of these other members of the microenvironment? Because maybe you know, just to play devil’s advocate, I wouldn’t treat a smoldering myeloma patient with my best most aggressive antimyeloma therapy, but maybe these are patients that I can modulate the microenvironment and have a completely different philosophy in the therapy and prevent them from ever having the end organ damage.

A. Keith Stewart, MB, ChB: Rafael, Tom mentioned that if you’re going to treat these people, maybe we should be aggressive. And Dr Maria-Victoria Mateos, MD, PhD, presented, at this meeting, an update on her very aggressive treatment approach to high-risk smoldering myeloma. Do you want to comment on that for the audience?

Rafael Fonseca, MD: Sure. So Maria-Victoria Mateos, MD, PhD, presented the GEM-CESAR trial, which is an approach that states we will give you the best treatment available, because this treatment would be the best treatment that’s available for active myeloma. So for the audience it’s KRd followed by stem cell transplant. So carfilzomib, lenalidomide, and dexamethasone followed by autologous stem cell transplant, followed by more of the same of induction as consolidation, then to be followed by lenalidomide-dexamethasone maintenance. Not surprisingly they achieve a very high rate of response, and you know, the patients obviously get deep control of their disease. But the key question remains: Who are those patients that need to be treated? I think as these trials have evolved over the years, maybe for some of those patients nowadays we would consider those who are in need of treatment, and maybe for some of those patients we would say they’re not quite there yet for treatment.

Now Dr Mateos is paving the way in telling us that you probably should consider treatment of early myeloma, or smoldering myeloma, with your original publication with lenalidomide. Again, you know about the stringent CR rate, and over 30% of patients get to a high rate of MRD negativity. So I think the question is not whether we have the tools. The real question is, when do we use them? And that goes back to the origin of our conversation. We can’t go back to the 1970s when you had 3 lines of criteria. So we have the criteria, we have the genetics, we have the dynamic changes over time. And then we need particularly 2 biomarkers: free light chain for renal dominance and we need a good biomarker for bone disease, which we unfortunately don’t have.

A. Keith Stewart, MB, ChB: Yeah, I think I saw a patient of yours a couple of weekends ago, who we were following and you were about to start treatment, and then the patient very quickly developed some renal failure so you had to…Sara and I get worried when the free light chains are getting high and if there’s any movement in the creatinine.

I kind of got the sense from the panel that people are still a little bit reluctant to treat smoldering myeloma, and that watchful waiting, for the community, is probably still the safest bet if you’re not entering a patient in a clinical trial. Would people agree with that?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yeah, I think so. I think the key, as you said, is watchful waiting. And I was going to say years ago watchful waiting could be 3 months or 6 months, and I think I would like to argue that at least for the first 3 months you’re actually maybe more aggressive in your watchful waiting and really make sure, because that 3-month period, it’s important…

A. Keith Stewart, MB, ChB: Because every so often you’ll find a patient who you think needs treatment and 10 years later you’re still watching. So I think those are important, and we define those patients.

Transcript Edited for Clarity

SELECTEDLANGUAGE

Transcript:

A. Keith Stewart, MB, ChB: So throughout this meeting there were quite a few abstracts addressing clinical trials with which an attempt was made to change the natural history of smoldering myeloma. And one of them that caught my attention was the use of elotuzumab in combination with lenalidomide and dexamethasone. Do you want to comment on that, Adriana?

Adriana Rossi, MD: Well I think it’s nice, both the ELO study, ELO/RD and the IXARD, which were the 2… Ixazomib, thank you. They give us an opportunity. We’re moving earlier and treating patients before they have end organ damage, which is much more palatable now that therapies are so well tolerated. And what I really liked about both of these studies is that they’re adding on correlative studies and other ways for us to inform and learn about the disease process. And, what is it? Can we distinguish which patients do benefit, which ones could maybe get away without therapy, and that maybe it’s not such a clear cut-off but it’s a plasmacytosis, an exact number? You know I think we have good data and guidelines to support certain clear definitions but in clinical practice I think we all sort of have a sense of this patient is about to get themselves into trouble and maybe someone with 50% rather than 60% in the marrow would be appropriate. But I really look forward to all of this other data, like the exome sequencing and RNA data that could maybe help us understand the patients better.

A. Keith Stewart, MB, ChB: So my take on these trials is that they all of course show a fairly high response rate. They all seem to trend towards decreasing the time to which you get myeloma. Were there any, Tom, in particular, that stood out for you that were interesting?

Thomas Martin, MD: Yeah. So what I would say about those 2 trials are that both actually in my mind had relatively low rates of complete response [CR]. And I think if we’re going to treat smoldering myeloma, and we’re not going to call it smoldering any more, we’re going to call it myeloma, let’s treat it with our best regimens. And we’ll talk more later about what our best regimens are for newly diagnosed myeloma, but I think I would be more aggressive in this patient population. And I think that we have data with RVd [lenalidomide, bortezomib, and dexamethasone] and a lot of data now with KRd [carfilzomib plus lenalidomide and dexamethasone], and now we’re getting data with quadruplets. And so I think my take on this is that if I’m going to treat them, I’m going to treat them with a more potent induction regimen.

A. Keith Stewart, MB, ChB: Do you feel that they’re being undertreated with these regimens then?

Thomas Martin, MD: I’m not sure if it’s undertreated, but I think we could treat them better and try to induce a higher rate of complete response. I mean at the end of the day we’re going to be looking at minimal residual disease—MRD-negativity. I don’t think we’re going to get the same MRD negativity from these 2 regimens—ELO, lenalidomide, and dexamethasone, or ixazomib, lenalidomide, and dexamethasone.

A. Keith Stewart, MB, ChB: So I listened to the presentation yesterday, particularly the elotuzumab, lenalidomide, and dexamethasone presentation, Faith, and one thing that struck me was that there were 2 deaths out of the 50 patients, but both looked to me like they were likely therapy related, with diabetic ketoacidosis and myocardial infarction. I guess that’s the concern, right? You’re overtreating and people who have a decade-long expectation of survival are being put at risk. What do you think of that?

Faith Davies, MD, MBBCh, MRCP, FRCPath: That’s why we have to really tighten up those criteria. I think that we know these drugs are safe and effective, but we really have to make sure that we’re treating those patients that are myeloma, and are not going to be those stable cases. So there’s definitely some fine-tuning there. And I think my own feeling is that we’re never going to get very strict guidance, and to some extent, it is going to be a little bit more of a gut feeling. I think as you said earlier, you know maybe at 50% and 60% and saying, “This is 50% and this is 60%, I shouldn’t treat,” I’m not sure that’s the way it’s going to be. I think it’s going to be a little bit more of see the patients and monitor them really closely so that we can pick out the best one.

A. Keith Stewart, MB, ChB: And Adriana you mentioned the correlative studies. I mean one thing that would concern me would potentially be breeding clonal evolution and drug resistance, which I guess we’ll learn from those studies.

Adriana Rossi, MD: We will, and, again, looking not only at the plasma cells. I think the more we learn about myeloma, it’s not really about the tumor cells themselves but the effect they have on the neighborhood. And what is the behavior of these other members of the microenvironment? Because maybe you know, just to play devil’s advocate, I wouldn’t treat a smoldering myeloma patient with my best most aggressive antimyeloma therapy, but maybe these are patients that I can modulate the microenvironment and have a completely different philosophy in the therapy and prevent them from ever having the end organ damage.

A. Keith Stewart, MB, ChB: Rafael, Tom mentioned that if you’re going to treat these people, maybe we should be aggressive. And Dr Maria-Victoria Mateos, MD, PhD, presented, at this meeting, an update on her very aggressive treatment approach to high-risk smoldering myeloma. Do you want to comment on that for the audience?

Rafael Fonseca, MD: Sure. So Maria-Victoria Mateos, MD, PhD, presented the GEM-CESAR trial, which is an approach that states we will give you the best treatment available, because this treatment would be the best treatment that’s available for active myeloma. So for the audience it’s KRd followed by stem cell transplant. So carfilzomib, lenalidomide, and dexamethasone followed by autologous stem cell transplant, followed by more of the same of induction as consolidation, then to be followed by lenalidomide-dexamethasone maintenance. Not surprisingly they achieve a very high rate of response, and you know, the patients obviously get deep control of their disease. But the key question remains: Who are those patients that need to be treated? I think as these trials have evolved over the years, maybe for some of those patients nowadays we would consider those who are in need of treatment, and maybe for some of those patients we would say they’re not quite there yet for treatment.

Now Dr Mateos is paving the way in telling us that you probably should consider treatment of early myeloma, or smoldering myeloma, with your original publication with lenalidomide. Again, you know about the stringent CR rate, and over 30% of patients get to a high rate of MRD negativity. So I think the question is not whether we have the tools. The real question is, when do we use them? And that goes back to the origin of our conversation. We can’t go back to the 1970s when you had 3 lines of criteria. So we have the criteria, we have the genetics, we have the dynamic changes over time. And then we need particularly 2 biomarkers: free light chain for renal dominance and we need a good biomarker for bone disease, which we unfortunately don’t have.

A. Keith Stewart, MB, ChB: Yeah, I think I saw a patient of yours a couple of weekends ago, who we were following and you were about to start treatment, and then the patient very quickly developed some renal failure so you had to…Sara and I get worried when the free light chains are getting high and if there’s any movement in the creatinine.

I kind of got the sense from the panel that people are still a little bit reluctant to treat smoldering myeloma, and that watchful waiting, for the community, is probably still the safest bet if you’re not entering a patient in a clinical trial. Would people agree with that?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yeah, I think so. I think the key, as you said, is watchful waiting. And I was going to say years ago watchful waiting could be 3 months or 6 months, and I think I would like to argue that at least for the first 3 months you’re actually maybe more aggressive in your watchful waiting and really make sure, because that 3-month period, it’s important…

A. Keith Stewart, MB, ChB: Because every so often you’ll find a patient who you think needs treatment and 10 years later you’re still watching. So I think those are important, and we define those patients.